PRDX1

In crisis, the nucleus calls antioxidant enzymes to the rescue. The nucleus being metabolically active is a profound paradigm shift with implications for cancer research. In crisis, the nucleus calls antioxidant enzymes to the rescue. The nucleus being metabolically active is a profound paradigm shift with implications for cancer research. Summary points Main text A typical human cell is metabolically active, roaring with chemical reactions that convert nutrients into energy and useful products that sustain life. These reactions also create reactive oxygen species, dangerous by-products like hydrogen peroxide which damage the building blocks of DNA in the same way oxygen and water corrode metal and form rust. Just how buildings collapse from the cumulative effect of rust, reactive oxygen species threatens a genome's integrity. Cells are thought to delicately balance their energy needs and avoid damaging DNA by containing metabolic activity outside the nucleus and within the cytoplasm and mitochondria. Antioxidant enzymes are deployed to mop up reactive oxygen species at their source before they reach DNA, a defensive strategy that protects the roughly 3 billion nucleotides from suffering potentially catastrophic mutations. If DNA damage occurs anyway, cells pause momentarily and carry out repairs, synthesising new building blocks and filling in the gaps. Despite the central role of cellular metabolism in maintaining genome integrity, there has been no systematic, unbiased study on how metabolic perturbations affect the DNA damage and repair process. This is particularly important for diseases like cancer, characterised by their ability to hijack metabolic processes for unfettered growth. A research team led by Sara Sdelci at the Centre for Genomic Regulation (CRG) in Barcelona and Joanna Loizou at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna and the Medical University of Vienna addressed this challenge by carrying out various experiments to identify which metabolic enzymes and processes are essential for a cell's DNA damage response. The findings are published today in the journal Molecular Systems Biology. The researchers experimentally induced DNA damage in human cell lines using a common chemotherapy medication known as etoposide. Etoposide works by breaking DNA strands and blocking an enzyme which helps repair the damage. Surprisingly, inducing DNA damage resulted in reactive oxygen species being generated and accumulating inside the nucleus. The researchers observed that cellular respiratory enzymes, a major source of reactive oxygen species, relocated from the mitochondria to the nucleus in response to DNA damage. The findings represent a paradigm shift in cellular biology because it suggests the nucleus is metabolically active. "Where there's smoke there's fire, and where there's reactive oxygen species there are metabolic enzymes at work. Historically, we've thought of the nucleus as a metabolically inert organelle that imports all its needs from the cytoplasm, but our study demonstrates that another type of metabolism exists in cells and is found in the nucleus," says Dr. Sara Sdelci, corresponding author of the study and Group Leader at the Centre for Genomic Regulation. The researchers also used CRISPR-Cas9 to identify all the metabolic genes that were important for cell survival in this scenario. These experiments revealed that cells order the enzyme PRDX1, an antioxidant enzyme also normally found in mitochondria, to travel to the nucleus and scavenge reactive oxygen species present to prevent further damage. PRDX1 was also found to repair the damage by regulating the cellular availability of aspartate, a raw material that is critical for synthesising nucleotides, the building blocks of DNA. "PRDX1 is like a robotic pool cleaner. Cells are known to use it to keep their insides 'clean' and prevent the accumulation of reactive oxygen species, but never before at the nuclear level. This is evidence that, in a state of crisis, the nucleus responds by appropriating mitochondrial machinery and establishes an emergency rapid-industrialisation policy," says Dr. Sdelci. The findings can guide future lines of cancer research. Some anti-cancer drugs, such as etoposide used in this study, kill tumour cells by damaging their DNA and inhibiting the repair process. If enough damage accumulates, the cancer cell initiates a process where it autodestructs. During their experiments, the researchers found that knocking out metabolic genes critical for cellular respiration -- the process that generates energy from oxygen and nutrients -- made normal healthy cells become resistant to etoposide. The finding is important because many cancer cells are glycolytic, meaning that even in the presence of oxygen they generate energy without doing cellular respiration. This means etoposide, and other chemotherapies with a similar mechanism, is likely to have a limited effect in treating glycolytic tumours. The authors of the study call for the exploration of new strategies such as dual treatment combining etoposide with drugs that also boost the generation of reactive oxygen species to overcome drug resistance and kill cancer cells faster. They also hypothesise that combining etoposide with inhibitors of nucleotide synthesis processes could potentiate the effect of the drug by preventing the repair of DNA damage and ensuring cancer cells self-destruct correctly. Dr. Joanna Loizou, corresponding author and Group Leader at the Centre for Molecular Medicine and the Medical University of Vienna, highlights the value of taking data-driven approaches to uncover new biological processes. 'By using unbiased technologies such as CRISPR-Cas9 screening and metabolomics, we have learnt about how the two fundamental cellular processes of DNA repair and metabolism are intertwined. Our findings shed light on how targeting these two pathways in cancer might improve therapeutic outcomes for patients'.

XI'AN, China, Oct. 25, 2022 /PRNewswire/ -- Although medicine and pharmacology have tremendously progressed over the past few decades, there are still no effective treatment options for certain complex diseases, including cancer, diabetes, and hepatic fibrosis. Researchers, however, continue to reveal mechanisms contributing to the development of these diseases, as well as potential drug targets, helping us develop better therapies. The latest issue of the Journal of Pharmaceutical Analysis features three articles on cutting-edge research targeting challenging diseases. The first study, published in Volume 12, Issue 4 of the journal in August 2022, was conducted by researchers from China and Singapore. They focused on 18beta-glycyrrhetinic acid (18β-GA), a compound naturally occurring in the plant Glycyrrhiza uralensis Fisch, whose root is widely used in traditional Asian medicine to treat hepatic diseases. Through multiple experiments, they demonstrated that 18β-GA can induce cell death in hepatic stellate cells, which are drivers of hepatic fibrosis, by targeting the antioxidants peroxiredoxin 1 and 2 and triggering oxidative stress in the cells. This has important medical implications, as the researchers commented: "Our findings provide strong evidence for the further development of 18β-GA as a therapeutic drug for the treatment of hepatic fibrosis. Understanding the underlying mechanisms of disease development have helped develop better therapeutics for liver diseases, which lead to almost 2 million deaths worldwide every year." In the second article, a review which was published in Volume 12, Issue 4 of the journal in August 2022, researchers from India summarized the latest knowledge on the role of human islet amyloid polypeptide (hIAPP) in the progression of type-2 diabetes mellitus (T2DM). The misfolding and aggregation of hIAPP into amyloid fibrils in the pancreas is one of the pathological hallmarks of T2DM and understanding why it happens, how it affects pancreatic cells, and how it can be stopped or reverted is essential in the context of T2DM. "Designing drugs that prevent hIAPP aggregation or that can eliminate already formed amyloid aggregates would likely help in the management of T2DM. Moreover, these drugs could be repurposed in the future for targeting other protein-misfolding disorders because of the common mechanism underlying these pathologies," the researchers remarked. In the final study, published in Volume 12, Issue 4 of the journal in August 2022, researchers from China screened 43 fluoroquinolone derivatives and tested them as microRNA-21 inhibitors to find a promising anti-cancer compound. Many types of tumor cells overexpress microRNA-21, making it a potential drug target in cancer therapy. Out of all the compounds tested, one named 'A36' proved to be the best microRNA-21 inhibitor. Cell culture experiments showed that A36 produced many of the outcomes that one would hope for in a cancer drug. "At the cellular level, A36 displayed moderate antiproliferative activity against six tumor cell lines, significantly induced apoptosis, arrested cell division, and inhibited colony formation of cancer cells, but exhibited no cytotoxic effects in healthy cell lines," the researchers highlighted. In summary, these studies help explain the pathogenesis of complex diseases like diabetes, cancer, and liver fibrosis while exploring new approaches of treatment and drug targets. Further research in this field will eventually help doctors treat people who suffer from these complex diseases. Reference DOI: Title of original paper: 18beta-glycyrrhetinic acid induces ROS-mediated apoptosis to ameliorate hepatic fibrosis by targeting PRDX1/2 in activated HSCs Journal: Journal of Pharmaceutical Analysis Contact: Fen Qiu +86-131-5206-8068 347162@email4pr.com

Medical researchers have identified a new type of microglia associated with stroke in the ischemia/reperfusion (I/R) injured brain. A research team, affiliated with UNIST has identified a new type of microglia associated with stroke in the ischemia/reperfusion (I/R) injured brain. This breakthrough has been led by Professor Sung Ho Park and his research team in the Department of Biological Sciences at UNIST, in collaboration with a research team, led by Professor Goo Taeg Oh from Ewha Womans University. Microglia, the primary immune cells in the central nervous system (CNS), are known to eliminate unwanted germs and debris and remove dying neurons. In this study, the research team classified a new type of microglia with enhanced antioxidant function and markers similar to those of disease-associated microglia (DAM), designated them as stroke-associated microglia (SAM). Through animal experiments, the research team demonstrated that the presence of the typical antioxidant gene, Peroxiredoxin-1 (Prdx1), protects against acute I/R injury and is required for SAM activation and the consequent reduction of microglial cell death and inflammatory responses. In addition, after performing transient middle cerebral artery occlusion (tMCAO) surgery to induce ischemic stroke in mice, the research team found that Prdx1−/− mice were more severely injured by acute I/R injury, as confirmed by TTC staining, neurological deficit scores, motor tests, and the survival rate, indicating that Prdx1 has a protective function. "In this study, we have, for the first time, identified a specialized and distinctive type of microglia with enhanced antioxidant function in stroke mice," says Professor Park. "Prdx1-dependent SAM may be a potential biomarker and therapeutic target for protecting microglial function and treating brain I/R injury," He adds, "Although this new cluster will require further study, our findings provide a new perspective that Prdx1-mediated microglial heterogeneity is important in ischemic stroke." This study has been jointly participated by Wonhyo Lee, a doctoral researcher within the Department of Biological Sciences at UNIST and Sinai Kim, a doctoral researcher within the Department of Life Sciences at Ewha Womans University, as first authors. Their findings have been published in the August 2022 issue of Redox Biology. This study was carried out with the support of the National Research Foundation of Korea (NRF).